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Activity dependent inhibition of TRPC1/4/5 channels by duloxetine involves voltage sensor-like domain

SYSNO ASEP	0559165
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	Activity dependent inhibition of TRPC1/4/5 channels by duloxetine involves voltage sensor-like domain
Author(s)	Zímová, Lucie (FGU-C)_{RID, ORCID} Ptáková, Alexandra (FGU-C) Mitro, Michal (FGU-C) Krůšek, Jan (FGU-C)_{RID, ORCID} Vlachová, Viktorie (FGU-C)_{RID, ORCID, SAI}
Article number	113262
Source Title	Biomedicine & Pharmacotherapy. - : Elsevier - ISSN 0753-3322 Roč. 152, August (2022)
Number of pages	11 s.
Language	eng - English
Country	FR - France
Keywords	TRPC channels ; TRPC5 ; Duloxetine ; inhibitor ; voltage sensor-like domain
OECD category	Physiology (including cytology)
R&D Projects	GA22-13750S GA ČR - Czech Science Foundation (CSF)
Method of publishing	Open access
Institutional support	FGU-C - RVO:67985823
UT WOS	000815801200004
EID SCOPUS	85132316348
DOI	10.1016/j.biopha.2022.113262
Annotation	Transient receptor potential canonical 5 (TRPC5) is a polymodal, calcium-permeable, nonselective ion channel that is expressed in the brain and 75 % of human sensory neurons. Its pharmacological or genetic inhibition leads to the relief of neuropathic and inflammatory pain. The clinically approved drug duloxetine is superior to other serotonin and norepinephrine reuptake inhibitors at managing painful neuropathies, but it is not known why. Here we ask whether the TRPC5 receptor is modulated by duloxetine and may contribute to its analgesic effect. Electrophysiological measurements of heterologously expressed human TRPC5 in HEK293T cells were performed to evaluate the effect of duloxetine. The interaction site was identified by molecular docking and molecular dynamics simulations in combination with point mutagenesis. We found that duloxetine inhibits TRPC5 in a concentration-dependent manner with a high potency (IC50 = 0.54 ± 0.03 µM). Our data suggest that duloxetine binds into a voltage sensor-like domain. For the interaction, Glu418 exhibited particular importance due to putative hydrogen bond formation. Duloxetine effectively inhibits TRPC5 currents induced by cooling, voltage, direct agonists and by the stimulation of the PLC pathway. The finding that this TRPC5 inhibitor is widely used and well tolerated provides a scaffold for new pain treatment strategies.
Workplace	Institute of Physiology
Contact	Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400
Year of Publishing	2023
Electronic address	https://doi.org/10.1016/j.biopha.2022.113262

Number of the records: 1